Insulin resistance plays a key role in the pathogenesis of type 2 diabetes, a disease now reaching epidemic proportions and anticipated to affect 220 million people worldwide by 2010. Thus, elucidating the factors that alter insulin sensitivity has important public health implications. While epidemiologic studies consistently demonstrate an inverse relationship between insulin resistance and testosterone (T) levels in men, data on causality are lacking. In addition, it is unclear whether T might modulate insulin action by a direct effect mediated through the androgen receptor or an indirect effect mediated by aromatization to estradiol (E2). Thus, the overall goal of this proposal is to define the role of gonadal sex steroids in modulating insulin action in men. Specific Aim (SA) #1 will examine the impact of acute (24 hours) and short-term (4 weeks) suppression of sex steroids on insulin sensitivity in normal men (Protocol 1). A gonadotropin-releasing hormone antagonist will be used to induce hypogonadism. Changes in insulin sensitivity will be assessed by a hyperinsulinemic-euglycemic clamp. The mechanisms underlying changes in insulin sensitivity will be explored by analyzing changes in body composition, and detailed studies of fat metabolism (rates of lipolysis & lipid oxidation) and skeletal muscle (muscle fiber type, intramyocellular lipid content, & gene expression profiles). Protocol 2 will examine the impact of 3 months of T therapy on all components of the metabolic syndrome (SA #2), the mechanism underlying any changes in insulin sensitivity using the methods outlined for SA #1, and the role of E2 in mediating the effect of T on insulin sensitivity (SA# 3). The present study, by combining carefully designed physiologic experiments with state of the art genetic and imaging studies, affords the opportunity to determine, if and how, T modulates insulin sensitivity in men. It is currently estimated that 20% of men over 60 years of age have low T levels. Therefore, if low T levels are shown to play a role in the pathogenesis of insulin resistance, T may well represent an important therapeutic modality for both preventing and treating the metabolic syndrome and type 2 diabetes in men. [unreadable] [unreadable] [unreadable]